Stephanie Kremp

Target volume definition for 18F-FDG PET-positive lymph nodes in radiotherapy of patients with non-small cell lung cancer

PurposeFDG PET is increasingly used in radiotherapy planning. Recently, we demonstrated substantial differences in target volumes when applying different methods of FDG-based contouring in primary lung tumours (Nestle et al., J Nucl Med 2005;46:1342–8). This paper focusses on FDG-positive mediastinal lymph nodes (LNPET).MethodsIn our institution, 51 NSCLC patients who were candidates for radiotherapy prospectively underwent staging FDG PET followed by a thoracic PET scan in the treatment position and a planning CT. Eleven of them had 32 distinguishable non-confluent mediastinal or hilar nodal FDG accumulations (LNPET). For these, sets of gross tumour volumes (GTVs) were generated at both acquisition times by four different PET-based contouring methods (visual: GTVvis; 40% SUVmax: GTV40; SUV=2.5: GTV2.5; target/background (T/B) algorithm: GTVbg).ResultsAll differences concerning GTV sizes were within the range of the resolution of the PET system. The detectability and technical delineability of the GTVs were significantly better in the late scans (e.g. p = 0.02 for diagnostic application of SUVmax = 2.5; p = 0.0001 for technical delineability by GTV2.5; p = 0.003 by GTV40), favouring the GTVbg method owing to satisfactory overall applicability and independence of GTVs from acquisition time. Compared with CT, the majority of PET-based GTVs were larger, probably owing to resolution effects, with a possible influence of lesion movements.ConclusionFor nodal GTVs, different methods of contouring did not lead to clinically relevant differences in volumes. However, there were significant differences in technical delineability, especially after early acquisition. Overall, our data favour a late acquisition of FDG PET scans for radiotherapy planning, and the use of a T/B algorithm for GTV contouring.

FDG-PET-BASED RADIOTHERAPY PLANNING IN LUNG CANCER: OPTIMUM BREATHING PROTOCOL AND PATIENT POSITIONING—AN INTRAINDIVIDUAL COMPARISON

PURPOSE Fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET) and PET/computed tomography (CT) are increasingly used for radiotherapy (RT) planning in patients with non-small-cell lung carcinoma. The planning process often is based on separately acquired FDG-PET/CT and planning CT scans. We compared intraindividual differences between PET acquired in diagnostic (D-PET) and RT treatment position (RT-PET) coregistered with planning CTs acquired using different breathing protocols. METHODS AND MATERIALS Sixteen patients with non-small-cell lung carcinoma underwent two PET acquisitions (D-PET and RT-PET) and three planning CT acquisitions (expiration [EXP], inspiration [INS], and mid-breath hold [MID]) on the same day. All scans were rigidly coregistered, resulting in six fused data sets: D-INS, D-EXP, D-MID, RT-INS, RT-EXP, and RT-MID. Fusion accuracy was assessed by three readers at eight anatomic landmarks, lung apices, aortic arch, heart, spine, sternum, carina, diaphragm, and tumor, by using an alignment score ranging from 1 (no alignment) to 5 (exact alignment). RESULTS The RT-PET showed better alignment with any CT than D-PET (p < 0.001). With regard to breathing, RT-MID showed the best mean alignment score (3.7 +/- 1.0), followed by RT-EXP (3.5 +/- 0.9) and RT-INS (3.0 +/- 0.8), with all differences significant (p < 0.001). Comparing alignment scores with regard to anatomic landmarks, the largest deviations were found at the diaphragm, heart, and apices. Overall, there was fair agreement (kappa = 0.48; p < 0.001) among the three readers. CONCLUSIONS Significantly better fusion of PET and planning CT can be reached with PET acquired in the RT position. The best intraindividual fusion results are obtained with the planning CT performed during mid-breath hold. Our data justify the acquisition of a separate planning PET in RT treatment position if only a diagnostic PET scan is available.

F-18-FDG-PET Confined Radiotherapy of Locally Advanced NSCLC With Concomitant Chemotherapy: Results of the PET-PLAN Pilot Trial

PURPOSE The integration of fluoro-deoxy-D-glucose positron emission tomography (FDG-PET) in the process of radiotherapy (RT) planning of locally advanced non-small-cell lung cancer (NSCLC) may improve diagnostic accuracy and minimize interobserver variability compared with target volume definition solely based on computed tomography. Furthermore, irradiating only FDG-PET-positive findings and omitting elective nodal regions may allow dose escalation by treating smaller volumes. The aim of this prospective pilot trial was to evaluate the therapeutic safety of FDG-PET-based RT treatment planning with an autocontour-derived delineation of the primary tumor. METHODS AND MATERIALS Eligible patients had Stages II-III inoperable NSCLC, and simultaneous, platinum-based radiochemotherapy was indicated. FDG-PET and computed tomography acquisitions in RT treatment planning position were coregistered. The clinical target volume (CTV) included the FDG-PET-defined primary tumor, which was autodelineated with a source-to-background algorithm, plus FDG-PET-positive lymph node stations. Limited by dose restrictions for normal tissues, prescribed total doses were in the range of 66.6 to 73.8 Gy. The primary endpoint was the rate of out-of-field isolated nodal recurrences (INR). RESULTS As per intent to treat, 32 patients received radiochemotherapy. In 15 of these patients, dose escalation above 66.6 Gy was achieved. No Grade 4 toxicities occurred. After a median follow-up time of 27.2 months, the estimated median survival time was 19.3 months. During the observation period, one INR was observed in 23 evaluable patients. CONCLUSIONS FDG-PET-confined target volume definition in radiochemotherapy of NSCLC, based on a contrast-oriented source-to-background algorithm, was associated with a low risk of INR. It might provide improved tumor control because of dose escalation.

Nonrigid Versus Rigid Registration of Thoracic 18F-FDG PET and CT in Patients with Lung Cancer: An Intraindividual Comparison of Different Breathing Maneuvers

In lung cancer, 18F-FDG PET, CT, and 18F-FDG PET/CT are used for noninvasive staging and therapy planning. Even with improved image registration techniques—especially in the modern hybrid PET/CT scanners—inaccuracies in the fusion process may occur, leading to errors in image interpretation. The aim of this study was to investigate by an intraindividual analysis whether, in comparison with a rigid algorithm, a nonrigid registration algorithm improves the quality of fusion between 18F-FDG PET and CT. Methods: Sixteen patients with histologically proven non–small cell lung cancer underwent a thoracic 18F-FDG PET acquisition in radiotherapy treatment position and 3 CT acquisitions (expiration, inspiration, and mid breath-hold) on the same day. All scans were registered with rigid and nonrigid procedures, resulting in 6 fused datasets: rigid inspiration, rigid expiration, rigid mid breath-hold, nonrigid inspiration, nonrigid expiration, and nonrigid mid breath-hold. The quality of alignment was assessed by 3 experienced readers at 8 anatomic landmarks: lung apices, aortic arch, heart, spine, sternum, carina, diaphragm, and tumor using an alignment score ranging from 1 (no alignment) to 5 (exact alignment). Results: Nonrigid PET/CT showed better alignment than rigid PET/CT (3.5 ± 0.7 vs. 3.3 ± 0.7, P < 0.001). Regarding the breathing maneuver, no difference between nonrigid mid breath-hold and rigid mid breath-hold was observed. In contrast, the alignment quality significantly improved from rigid expiration to nonrigid expiration (3.4 ± 0.7 vs. 3.6 ± 0.7, P < 0.001) and from rigid inspiration to nonrigid inspiration (3.1 ± 0.7 vs. 3.3 ± 0.7, P < 0.001). With regard to individual landmarks, an improvement in fusion quality through the use of nonrigid registration was obvious at the lung apices, carina, and aortic arch. Conclusion: The alignment quality of thoracic 18F-FDG PET/CT exhibits a marked dependence on the breathing maneuver performed during the CT acquisition, as demonstrated in an intraindividual comparison. Nonrigid registration is a significant improvement over rigid registration if the CT is performed during full inspiration or full expiration. The best fusion results are obtained with the CT performed at mid breath-hold using rigid registration, without an improvement using nonrigid algorithms.

The Impact of Diffusion-Weighted MRI on the Definition of Gross Tumor Volume in Radiotherapy of Non-Small-Cell Lung Cancer

Objective The study was designed to evaluate diffusion-weighted magnetic resonance imaging (DWI) vs. PET-CT of the thorax in the determination of gross tumor volume (GTV) in radiotherapy planning of non-small-cell lung cancer (NSCLC). Materials and Methods Eligible patients with NSCLC who were supposed to receive definitive radio(chemo)therapy were prospectively recruited. For MRI, a respiratory gated T2-weighted sequence in axial orientation and non-gated DWI (b = 0, 800, 1,400 and apparent diffusion coefficient map [ADC]) were acquired on a 1.5 Tesla scanner. Primary tumors were delineated on FDG-PET/CT (stGTV) and DWI images (dwGTV). The definition of stGTV was based on the CT and visually adapted to the FDG-PET component if indicated (e.g., in atelectasis). For DWI, dwGTV was visually determined and adjusted for anatomical plausibility on T2w sequences. Beside a statistical comparison of stGTV and dwGTB, spatial agreement was determined with the “Hausdorff-Distance” (HD) and the “Dice Similarity Coefficient” (DSC). Results Fifteen patients (one patient with two synchronous NSCLC) were evaluated. For 16 primary tumors with UICC stages I (n = 4), II (n = 3), IIIA (n = 2) and IIIB (n = 7) mean values for dwGTV were significantly larger than those of stGTV (76.6 ± 84.5 ml vs. 66.6 ± 75.2 ml, p<0.01). The correlation of stGTV and dwGTV was highly significant (r = 0.995, p<0.001). Yet, some considerable volume deviations between these two methods were observed (median 27.5%, range 0.4–52.1%). An acceptable agreement between dwGTV and stGTV regarding the spatial extent of primary tumors was found (average HD: 2.25 ± 0.7 mm; DC 0.68 ± 0.09). Conclusion The overall level of agreement between PET-CT and MRI based GTV definition is acceptable. Tumor volumes may differ considerably in single cases. DWI-derived GTVs are significantly, yet modestly, larger than their PET-CT based counterparts. Prospective studies to assess the safety and efficacy of DWI-based radiotherapy planning in NSCLC are warranted.

Visualisation of Respiratory Tumour Motion and Co-Moving Isodose Lines in the Context of Respiratory Gating, IMRT and Flattening-Filter-Free Beams

Respiratory motion during percutaneous radiotherapy can be considered based on respiration-correlated computed tomography (4DCT). However, most treatment planning systems perform the dose calculation based on a single primary CT data set, even though cine mode displays may allow for a visualisation of the complete breathing cycle. This might create the mistaken impression that the dose distribution were independent of tumour motion. We present a movie visualisation technique with the aim to direct attention to the fact that the dose distribution migrates to some degree with the tumour and discuss consequences for gated treatment, IMRT plans and flattening-filter-free beams. This is a feasibility test for a visualisation of tumour and isodose motion. Ten respiratory phases are distinguished on the CT, and the dose distribution from a stationary IMRT plan is calculated on each phase, to be integrated into a movie of tumour and dose motion during breathing. For one example patient out of the sample of five lesions, the plan is compared with a gated treatment plan with respect to tumour coverage and lung sparing. The interplay-effect for small segments in the IMRT plan is estimated. While the high dose rate, together with the cone-shaped beam profile, makes the use of flattening-filter-free beams more problematic for conformal and IMRT treatment, it can be the option of choice if gated treatment is preferred. The different effects of respiratory motion, dose build-up and beam properties (segments and flatness) for gated vs. un-gated treatment can best be considered if planning is performed on the full 4DCT data set, which may be an incentive for future developments of treatment planning systems.

Magnetic Resonance Lymphography at 9.4 T Using a Gadolinium-Based Nanoparticle in Rats: Investigations in Healthy Animals and in a Hindlimb Lymphedema Model

Objectives Magnetic resonance lymphography (MRL) in small animals is a promising but challenging tool in preclinical lymphatic research. In this study, we compared the gadolinium (Gd)-based nanoparticle AGuIX with Gd-DOTA for interstitial MRL in healthy rats and in a chronic rat hindlimb lymphedema model. Materials and Methods A comparative study with AGuIX and Gd-DOTA for interstitial MRL was performed in healthy Lewis rats (n = 6). For this purpose, 75 &mgr;L of 3 mM AGuIX (containing 30 mM Gd-DOTA side residues) and 75 &mgr;L 30 mM Gd-DOTA were injected simultaneously in the right and left hindlimbs. Repetitive high-resolution, 3-dimensional time-of-flight gradient recalled echo MRL sequences were acquired over a period of 90 minutes using a 9.4 T animal scanner. Gadofosveset-enhanced MR angiography and surgical dissection after methylene blue injection served as supportive imaging techniques. In a subsequent proof-of-principle study, AGuIX-based MRL was investigated in a hindlimb model of chronic lymphedema (n = 4). Lymphedema of the right hindlimbs was induced by means of popliteal and inguinal lymphadenectomy and irradiation with 20 Gy. The nonoperated left hindlimbs served as intraindividual controls. Six, 10, and 14 weeks after lymphadenectomy, MRL investigations were performed to objectify lymphatic reorganization. Finally, skin samples of the lymphedematous and the contralateral control hindlimbs were analyzed by means of histology and immunohistochemistry. Results AGuIX-based MRL resulted in high-resolution anatomical depiction of the rodent hindlimb lymphatic system. Signal-to-noise ratio and contrast-to-noise ratio of the popliteal lymph node were increased directly after injection and remained significantly elevated for up to 90 minutes after application. AGuIX provided significantly higher and prolonged signal intensity enhancement as compared with Gd-DOTA. Furthermore, AGuIX-based MRL demonstrated lymphatic regeneration in the histopathologically verified chronic lymphedema model. Collateral lymphatic vessels were detectable 6 weeks after lymphadenectomy. Conclusions This study demonstrates that AGuIX is a suitable contrast agent for preclinical interstitial MRL in rodents. AGuIX yields anatomical imaging of lymphatic vessels with diameters greater than 200 &mgr;m. Moreover, it resides in the lymphatic system for a prolonged time. AGuIX may therefore facilitate high-resolution MRL-based analyses of the lymphatic system in rodents.